The Fellow on Call: The Heme/Onc Podcast

Episode 124: AML Series, Pt 10 — Allogeneic Transplant for AML
Date: December 11, 2024
Host: Rouleaux University Medical Center
Guest: Dr. Amer Kelker, Dana-Farber Cancer Institute

Episode Overview

This episode continues the discussion on allogeneic transplant in acute myeloid leukemia (AML), focusing on conditioning regimens, the role of MRD (measurable residual disease), maintenance therapies, graft versus host disease (GVHD), advancements in haploidentical transplantation, and addressing racial disparities in transplant outcomes. Dr. Amer Kelker offers evidence-based insights and practical pearls for trainees, clinicians, and anyone looking to deepen their understanding of modern transplant paradigms in AML.

Key Topics & Insights

1. Conditioning Regimens: Myeloablative vs. Reduced Intensity

(02:18–05:01)

• Definitions:

  • Myeloablative conditioning (MAC) uses higher doses of chemotherapy/radiation (e.g., Fludarabine/Bulsulfan "FluBu 4").
  • Reduced intensity conditioning (RIC) uses lower doses (e.g., "FluBu 2").
  • Regimens exist on a spectrum, not as strict categories.

• Study Comparisons:

  • BMT CTN 0901 (US study): Supported MAC in patients aged 18–65, showing superior overall survival compared to RIC, despite higher transplant-related mortality (TRM) with MAC.
  • European & German studies (e.g., EBMT’s RICMAC): Powered for TRM, not overall survival, found no difference—results possibly underpowered.

• Clinical Considerations:

  • Younger patients (<60–65): Generally favor MAC due to better outcomes.
  • Older patients (>60–65): TRM increases with MAC, net benefit diminishes.

• Quote:

  “For especially younger patients … will favor myeloablative transplants. For patients in the 60-65 range or even older, the data doesn’t quite bear out as favorably … and you start to lose the net benefit from the graft vs. leukemia effect.”
  — Dr. Amer Kelker, (04:20)

2. Total Body Irradiation (TBI) in Conditioning

(05:55–07:01)

• History & Use:

  • TBI was among the first conditioning regimens.
  • Provides low rates of graft rejection; mostly used in high-risk situations (e.g., sickle cell, prior antigen sensitization).

• Clinical Insight:

  “TBI-based regimens tend to have the lowest rates of graft rejections … if we’re going to use a reduced intensity transplant as opposed to an ablative transplant, we found that adding TBI can often reduce the risk.”
  — Dr. Kelker, (06:20)

• Special Note on Sickle Cell Disease:

  • Higher risk of secondary malignancies with RIC; MAC is favored at Dr. Kelker’s center for these patients.

3. The Role of MRD Testing in Transplant

(08:13–11:08)

• Current Practice:

  • MRD status (via flow cytometry or PCR, depending on mutation) critical for risk stratification pre-transplant.
  • No standardized methodology for MRD—centers rely on what’s available.

• MRD as a Decision Tool:

  • MRD-positive patients: Higher risk, benefit more from transplant.
  • MRD-negative patients: May do equally well with RIC vs. MAC.

• Specifics:

  • FLT3ITD PCR: Data suggests MRD-positive patients benefit from transplant even if ELN criteria consider their AML "favorable risk."
  • NPM1 tests available, but clonal evolution complicates long-term reliance.

• Quote:

  “I personally test MRD … understanding that patients that are MRD-positive are probably higher risk if they don’t have transplant. Transplant is considered an equalizer for MRD.”
  — Dr. Kelker, (10:01)

4. Maintenance Therapy Post-Transplant

(12:08–14:04)

• Trial Evidence:

  • SORMANE (subset with sorafenib): Phase 2, positive for overall survival, but significant GI toxicity.
  • MORPHO (gilteritinib): Large RCT, narrowly missed significance (p=0.051); initial data even suggested worse survival, causing concern.

• Current Approach:

  • Use is reserved for high-risk/MRD-positive patients.
  • Gilteritinib often preferred over sorafenib for better tolerability.

• Clinical Reflection:

  “…the concept of maintenance therapy is kind of anathema to our existence. The whole idea is that this is a curative therapy … so the idea of giving more [chemo] when they don’t have a relapse feels really bad.”
  — Dr. Kelker, (12:18)

5. Graft Versus Host Disease (GVHD): Acute & Chronic

(15:00–18:34)

• Manifestations:

  • Acute: Typically first 6 months; skin, GI, liver involvement.
  • Chronic: Starts ~6 months, peaks at 1 year; skin (scarring), mouth, eyes, lungs (bronchiolitis obliterans).

• Treatment Progress:

  • Steroids are first-line.
  • Second-line/new agents: Ibrutinib (less used in practice), ruxolitinib (acute/chronic), belumosudil (“resuroc,” ROCKstar trial).

• Note on New Therapies:

  • CSF1R inhibitors show promise; various systemic and inhaled therapies in development.

• Quote:

  “…chronic GVHD, I think of as a scarring disease … Acute GVHD is all T-cell mediated. Chronic is both T and B cell, leaning B-cell.”
  — Dr. Kelker, (16:49)

6. Haploidentical Transplants & Post-Transplant Cyclophosphamide

(18:34–20:52)

• Background:

  • Post-transplant cyclophosphamide (“PTCy”) revolutionized the safety of haploidentical (half-matched) transplantation.
  • Now used for unmatched as well as matched related/unrelated donors.

• Donor Selection Hierarchy:

  • First: Matched sibling
  • Second: Matched unrelated
  • Third: Haploidentical (often treated similarly to mismatched unrelated, i.e., 7/8 matches)

• Quote:

  “It’s really kind of taken the whole field by storm. It’s been considered to be a great equalizer for haplo[transplants] … where we see much less of a difference in GVHD risk.”
  — Dr. Kelker, (19:16)

7. Age Cut-Offs for Donors in Haploidentical Transplant

(21:11–22:10)

• General Rule:
  • Age limit for donors: Up to 60–65 years old to minimize risk of donor-derived secondary malignancies.
  • In adults, most haploidentical donors are children or young relatives.

8. Racial Disparities in Allogeneic Transplant

(22:10–25:00)

• Progress & Challenges:

  • Gaps in outcomes are narrowing—improvements in donor registries, trial diversity, and implicit bias training are helping.
  • Non-Hispanic Black patients still at significant disadvantage compared to Whites and other minorities.

• Key Barriers:

  • Fewer matched donors for minorities in registries.
  • Geographical/insurance access issues.
  • Socioeconomic factors, bias, unequal clinical trial representation.

• Action Steps:

  “More and more countries are developing donor databases … there’s a larger push to address implicit biases … as we get better at targeting our resources, I think we’ll start to close those gaps.”
  — Dr. Kelker, (24:05)

Notable Quotes & Memorable Moments

• “When you think about surrogate endpoints … the goal here is overall survival. Of course, TRM will be lower if you use less chemo.”
  — Vivek, (05:01)
• “MRD testing is on the brink of becoming something big, but we're just not quite there yet.”
  — Ronak, (14:04)
• “I think as we get better at targeting our resources and develop more resources for these patients, I think we’ll start to close [racial] gaps.”
  — Dr. Kelker, (24:35)

Timestamps for Key Segments

• Conditioning Regimens: 02:18 – 05:01
• Total Body Irradiation: 05:55 – 07:01
• MRD Testing in AML: 08:13 – 11:08
• Maintenance Therapy Post-Transplant: 12:08 – 14:04
• GVHD Overview & Management: 15:00 – 18:34
• Haploidentical Transplants & PTCy: 18:34 – 20:52
• Donor Age Considerations: 21:11 – 22:10
• Racial Disparities in Transplant: 22:10 – 25:00

Summary & Takeaways

Dr. Kelker shares up-to-date, nuanced guidance on the selection and management of conditioning regimens, integration of MRD into decision-making, evolving approaches to post-transplant maintenance, advancements in GVHD therapies, the democratizing impact of haploidentical transplantation with post-transplant cyclophosphamide, and efforts to address long-standing racial inequities in transplant access and outcomes.

This episode is a comprehensive, high-yield resource for understanding the latest thinking in allogeneic transplant for AML in 2024.